title: Co-occurrence of m.1555A>G and m.11778G>A mitochondrial DNA mutations in two Indian families with strikingly different clinical penetrance of Leber hereditary optic neuropathy.
abstract: BACKGROUND
  Mitochondrial DNA (mtDNA) mutations are known to cause Leber hereditary optic neuropathy (LHON). However, the co-occurrence of double pathogenic mutations with different pathological significance in pedigrees is a rare event.
  
  
  METHODS
  Detailed clinical investigation and complete mtDNA sequencing analysis was performed for two Indian families with LHON. The haplogroup was constructed based on evolutionarily important mtDNA variants.
  
  
  RESULTS
  We observed the existence of double pathogenic mutations (m.11778G>A and m.1555A>G) in two Indian LHON families, who are from different haplogroup backgrounds (M5a and U2e1), with different clinical penetrance of the disease (visual impairment). The m.11778G>A mutation in the MT-ND4 gene is associated primarily with LHON; whereas, m.1555A>G in the 12S rRNA gene has been reported with aminoglycoside-induced non-syndromic hearing loss.
  
  
  CONCLUSIONS
  The absence of hearing abnormality and widely varying clinical expression of LHON suggest additional nuclear modifier genes, environmental factors, and population heterogeneity might play an important role in the expression of visual impairment in these families.
authors.affiliation: CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India.
authors.forename: Nahid Akhtar
authors.initials: NA
authors.lastname: Khan
authors.forename: Periyasamy
authors.initials: P
authors.lastname: Govindaraj
authors.forename: Vuskamalla
authors.initials: V
authors.lastname: Jyothi
authors.forename: Angamuthu K
authors.initials: AK
authors.lastname: Meena
authors.forename: Kumarasamy
authors.initials: K
authors.lastname: Thangaraj
mesh_terms: D001483:Base Sequence; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D005190:Family; D005260:Female; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007194:India; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics*; D010375:Pedigree; D019683:Penetrance; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D055815:Young Adult
chemical_list: D004272:DNA, Mitochondrial